目的探讨低级别嗜酸细胞性肾肿瘤(low-grade oncocytic tumor of kidney,LOT)的临床病理特征、免疫表型、分子改变及鉴别诊断,同时寻找敏感的客观指标辅助诊断。方法收集14例LOT的临床病理资料,行光镜观察、免疫组化染色等,其中8例送检...目的探讨低级别嗜酸细胞性肾肿瘤(low-grade oncocytic tumor of kidney,LOT)的临床病理特征、免疫表型、分子改变及鉴别诊断,同时寻找敏感的客观指标辅助诊断。方法收集14例LOT的临床病理资料,行光镜观察、免疫组化染色等,其中8例送检了高通量靶向基因突变检测。结果14例中男性4例,女性10例,年龄46~88岁,中位年龄57.5岁,平均61.1岁,平均随访6~90个月,1例患者肿瘤复发,其余无瘤生存;镜下肿瘤以实性片状、小巢状结构为主,常兼有大片出血与疏松水肿区域;胞质嗜酸性、细颗粒状,细胞核圆,核仁不明显,常见核周空晕,不易见核皱缩、核多形。免疫表型:LOT免疫表型一致性较好,所有病例均呈现经典的CK7+/CD117-表型(14/14,100%);CD10、CK20、vimentin均呈阴性(0/14,0);Ki67增殖指数1%~3%;此外,新提出的鉴别抗体GPNMB(14/14,100%)弥漫强阳性;GATA3(14/14,100%)至少部分区域中等程度核阳性。高通量测序:8例送检NGS测序,均有MTOR或TSC1基因致病性/可能致病性突变(7例有MTOR基因突变,1例有TSC1基因突变)。结论LOT是一种低级别嗜酸性肿瘤,具有可辨识的形态学特点和免疫表型、分子特征,偏向惰性生物学行为,是一种独立的嗜酸性肿瘤亚型。展开更多
Bartter syndrome is a group of autosomal recessive renal tubular disorders;it has two types of presentation:antenatal and classic.The antenatal type presents as severe unexplained polyhydramnios in the second trimeste...Bartter syndrome is a group of autosomal recessive renal tubular disorders;it has two types of presentation:antenatal and classic.The antenatal type presents as severe unexplained polyhydramnios in the second trimester.This is due to fetal urinary losses of sodium,chloride,and potassium,leading to fetal polyuria.The classic type presents in the late neonatal or infancy stage,with dehydration,dyselectrolytemia,failure to thrive,and nephrocalcinosis.Antenatal scans are normal in such cases.Type I and II Bartter syndrome presents in the antenatal period,whereas type IV has a classic presentation.We describe an unusual case of type IVa Bartter syndrome presenting in the antenatal period,with severe polyhydramnios.The initial diagnosis was made based on amniotic fluid chloride levels and later confirmed by performing a genetic test.Genetic testing is important for confirming diagnosis and prognostication regarding the condition.展开更多
Next generation sequencing is currently a cornerstone of genetic testing in routine diagnostics,allowing for the detection of sequence variants with so far unprecedented large scale,mainly in genetically heterogenous ...Next generation sequencing is currently a cornerstone of genetic testing in routine diagnostics,allowing for the detection of sequence variants with so far unprecedented large scale,mainly in genetically heterogenous diseases,such as neurological disorders.It is a fast-moving field,where new wet enrichment protocols and bioinformatics tools are constantly being developed to overcome initial limitations.Despite the as yet undiscussed advantages,however,there are still some challenges in data analysis and the interpretation of variants.In this review,we address the current state of next generation sequencing diagnostic testing for inherited human disorders,particularly giving an overview of the available high-throughput sequencing approaches;including targeted,whole-exome and whole-genome sequencing;and discussing the main critical aspects of the bioinformatic process,from raw data analysis to molecular diagnosis.展开更多
Although whole-exome sequencing and whole-genome sequencing has tremendously improved our understanding of the genetic etiology of human disorders,about half of the patients still do not receive a molecular diagnosis....Although whole-exome sequencing and whole-genome sequencing has tremendously improved our understanding of the genetic etiology of human disorders,about half of the patients still do not receive a molecular diagnosis.The high fraction of variants with uncertain significance and the challenges of interpretation of noncoding variants have urged scientists to implement RNA sequencing(RNA-seq)in the diagnostic approach as a high throughput assay to complement genomic data with functional evidence.RNA-seq data can be used to identify aberrantly spliced genes,detect allele-specific expression,and identify gene expression outliers.Amongst eight studies utilizing RNA-seq,a mean diagnostic uplift of 15%has been reported.Here,we provide an overview of how RNA-seq has been implemented to aid in identifying the causal variants of Mendelian disorders.展开更多
Introduction Acute liver failure(ALF)is an uncommon disease in pediatric cases.Etiology includes infections,autoimmune diseases,inborn errors of metabolism,and intoxications.Metabolic disorders account for 25%of resol...Introduction Acute liver failure(ALF)is an uncommon disease in pediatric cases.Etiology includes infections,autoimmune diseases,inborn errors of metabolism,and intoxications.Metabolic disorders account for 25%of resolved cases.However,the etiology remains unknown in half of pediatric ALF[1].The recognition of molecular etiopathogenesis has been facilitated after the common use of next-generation sequencing techniques.Recently,biallelic variants in neuroblastoma-amplified sequence(NBAS),Leucyl-tRNA synthetase 1(LARS1),and RAD50-interacting protein(RINT1)were identified in recurrent ALF(RALF)[2–4].展开更多
Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome(NS)of different etiologies is critical for early clinical guidance.We employed whole-exome sequencing(WES)t...Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome(NS)of different etiologies is critical for early clinical guidance.We employed whole-exome sequencing(WES)to detect monogenic causes of NS in a multicenter cohort of 637 patients.In this study,a genetic cause was identified in 30.0%of the idiopathic steroid-resistant nephrotic syndrome(SRNS)patients.Other than congenital nephrotic syndrome(CNS),there were no significant differences in the incidence of monogenic diseases based on the age at manifestation.Causative mutations were detected in 39.5%of patients with focal segmental glomerulosclerosis(FSGS)and 9.2%of those with minimal change disease(MCD).In terms of the patterns in patients with different types of steroid resistance,a single gene mutation was identified in 34.8%of patients with primary resistance,2.9%with secondary resistance,and 71.4%of children with multidrug resistance.Among the various intensified immunosuppressive therapies,tacrolimus(TAC)showed the highest response rate,with 49.7%of idiopathic SRNS patients achieving complete remission.Idiopathic SRNS patients with monogenic disease showed a similar multidrug resistance pattern,and only 31.4%of patients with monogenic disease achieved a partial remission on TAC.During an average 4.1-year follow-up,21.4%of idiopathic SRNS patients with monogenic disease progressed to end-stage renal disease(ESRD).Collectively,this study provides evidence that genetic testing is necessary for presumed steroid-resistant and idiopathic SRNS patients,especially those with primary and/or multidrug resistance.展开更多
Background:Leber congenital amaurosis(LCA),primarily characterized by retinal degeneration is the most severe form of inherited retinal dystrophy(IRD)responsible for congenital blindness.The presence of phenotypic het...Background:Leber congenital amaurosis(LCA),primarily characterized by retinal degeneration is the most severe form of inherited retinal dystrophy(IRD)responsible for congenital blindness.The presence of phenotypic heterogeneity makes the diagnosis of LCA challenging,especially in the absence of pronounced disease pathognomonic,yet it can be well comprehended by employing molecular diagnosis.Therefore,the present study aimed to reveal the causative mutations in ten LCA patients with variable phenotypes using clinical exome sequencing(CES).Methods:CES was performed in ten unrelated LCA patients.Ophthalmic information and family history of all patients were obtained to make a meaningful interpretation.The clinical exome data was analyzed and prioritized using a bioinformatics pipeline to identify mutations,which was further validated by Sanger sequencing.Segregation analysis was also performed on available family members.Results:CES led to the identification of causative mutations in nine LCA patients.Seven patients harbored a mutation in six LCA candidate genes,including RPE65,LCA5(n=2),CRX,PRPH2,CEP290,and ALMS1,while two patients possess a mutation in IFT80 and RP1,known to cause other diseases.Three novel mutations in LCA5(c.1823del),CRX(c.848del)and CEP290(c.2483G>T)were identified.The current study reports for the first time,a mutation in PRPH2,CEP290,and ALMS1 from the Indian population.Additionally,we observed a novel association of LCA phenotype with IFT80 known to cause Jeune syndrome.Based on the genetic finding,the patient AS09,who harbored a mutation in the RP1 gene,was re-diagnosed with early-onset retinitis pigmentosa.Conclusion:In conclusion,the results underline the importance of CES in clinically diagnosed LCA patients with variable phenotypes.The correlation between mutations in candidate genes and clinical phenotypes,helps to refine the clinical diagnosis.However,molecular evaluation with a larger cohort of LCA patients is needed for better understanding of the mutational spectrum in southern Ind展开更多
Premenstrual dysphoric disorder(PMDD) affects nearly 5% of women of reproductive age. Symptomatic heterogeneity, together with largely unknown genetics, has greatly hindered its effective treatment. In the present stu...Premenstrual dysphoric disorder(PMDD) affects nearly 5% of women of reproductive age. Symptomatic heterogeneity, together with largely unknown genetics, has greatly hindered its effective treatment. In the present study, analysis of genomic sequencing-based copy number variations(CNVs) called from 100 kb white blood cell DNA sequence windows by means of semisupervized clustering led to the segregation of patient genomes into the D and V groups, which correlated with the depression and invasion clinical types,respectively, with 89.0% consistency. Application of diagnostic CNV features selected using the correlation-based machine learning method enabled the classification of the CNVs obtained into the D group, V group, total patient group, and control group with an average accuracy of 83.0%. The power of the diagnostic CNV features was 0.98 on average, suggesting that these CNV features could be used for the molecular diagnosis of the major clinical types of PMDD. This demonstrated concordance between the CNV profiles and clinical types of PMDD supported the validity of symptom-based diagnosis of PMDD for differentiating between its two major clinical types, as well as the predominantly genetic nature of PMDD with a host of overlaps between multiple susceptibility genes/pathways and the diagnostic CNV features as indicators of involvement in PMDD etiology.展开更多
The Patched 1(PTCH1)gene encodes a membrane receptor involved in the Hedge-hog(Hh)signaling pathway,an abnormal state of which may result in congenital defects or hu-man tumors.In this study,we conducted whole-exome s...The Patched 1(PTCH1)gene encodes a membrane receptor involved in the Hedge-hog(Hh)signaling pathway,an abnormal state of which may result in congenital defects or hu-man tumors.In this study,we conducted whole-exome sequencing on a three-generation Chinese family characterized with variable penetrance of orofacial clefts.A rare heterozygous variant in the PTCH1 gene(c.2833C>T p.R945X)was identified as a disease-associated mutation.Structural modeling revealed a truncation starting from the middle of the second extracellular domain of PTCH1 protein.This may damage its ligand recognition and sterol transportation abilities,thereby affecting the Hh signaling pathway.Biochemical assays indi-cated that the R945X protein had reduced stability compared to the wild-type in vitro.In addi-tion,we reviewed the locations and mutation types of PTCH1 variants in individuals with clefting phenotypes,and analyzed the associations between clefts and locations or types of variants within PTCH1.Our findings provide further evidence that PTCH1 variants result in or-ofacial clefts,and contributed to genetic counseling and clinical surveillance in this family.展开更多
Developments in genetics and genomics are progressing at an unprecedented speed.Twenty years ago,the human genome project provided the first glimpses into the human genome sequence and launched a new era of human gene...Developments in genetics and genomics are progressing at an unprecedented speed.Twenty years ago,the human genome project provided the first glimpses into the human genome sequence and launched a new era of human genetics.The emerging of next-generation sequencing(NGS)in 2005 then made possible comprehensive genetic testing such as exome sequencing and genome sequencing.Meanwhile,great efforts have been put into the optimization of bioinformatic pipelines to make increasingly speedy and accurate variant analyses based on NGS data.These advances in sequencing technologies and analytical methods have revolutionized the diagnostic odyssey of suspected hereditary diseases.More recently,the genotype-phenotype relationship and polygenic risk scores(PRSs)generated from genome-wide association studies have expanded our horizon from rare genetic mutations to a genomic landscape implicated by the combined effect of both rare variants and polymorphisms.At the same time,clinicians and genetic counselors are facing huge challenges conferred by overwhelming genomic knowledge and long sheets of testing reports for comprehensive genomic sequencing.The path toward the“next-generation”clinical genetics and genomics may underlie semiautomatic pipelines assisted by artificial intelligence techniques.展开更多
文摘目的探讨低级别嗜酸细胞性肾肿瘤(low-grade oncocytic tumor of kidney,LOT)的临床病理特征、免疫表型、分子改变及鉴别诊断,同时寻找敏感的客观指标辅助诊断。方法收集14例LOT的临床病理资料,行光镜观察、免疫组化染色等,其中8例送检了高通量靶向基因突变检测。结果14例中男性4例,女性10例,年龄46~88岁,中位年龄57.5岁,平均61.1岁,平均随访6~90个月,1例患者肿瘤复发,其余无瘤生存;镜下肿瘤以实性片状、小巢状结构为主,常兼有大片出血与疏松水肿区域;胞质嗜酸性、细颗粒状,细胞核圆,核仁不明显,常见核周空晕,不易见核皱缩、核多形。免疫表型:LOT免疫表型一致性较好,所有病例均呈现经典的CK7+/CD117-表型(14/14,100%);CD10、CK20、vimentin均呈阴性(0/14,0);Ki67增殖指数1%~3%;此外,新提出的鉴别抗体GPNMB(14/14,100%)弥漫强阳性;GATA3(14/14,100%)至少部分区域中等程度核阳性。高通量测序:8例送检NGS测序,均有MTOR或TSC1基因致病性/可能致病性突变(7例有MTOR基因突变,1例有TSC1基因突变)。结论LOT是一种低级别嗜酸性肿瘤,具有可辨识的形态学特点和免疫表型、分子特征,偏向惰性生物学行为,是一种独立的嗜酸性肿瘤亚型。
文摘Bartter syndrome is a group of autosomal recessive renal tubular disorders;it has two types of presentation:antenatal and classic.The antenatal type presents as severe unexplained polyhydramnios in the second trimester.This is due to fetal urinary losses of sodium,chloride,and potassium,leading to fetal polyuria.The classic type presents in the late neonatal or infancy stage,with dehydration,dyselectrolytemia,failure to thrive,and nephrocalcinosis.Antenatal scans are normal in such cases.Type I and II Bartter syndrome presents in the antenatal period,whereas type IV has a classic presentation.We describe an unusual case of type IVa Bartter syndrome presenting in the antenatal period,with severe polyhydramnios.The initial diagnosis was made based on amniotic fluid chloride levels and later confirmed by performing a genetic test.Genetic testing is important for confirming diagnosis and prognostication regarding the condition.
文摘Next generation sequencing is currently a cornerstone of genetic testing in routine diagnostics,allowing for the detection of sequence variants with so far unprecedented large scale,mainly in genetically heterogenous diseases,such as neurological disorders.It is a fast-moving field,where new wet enrichment protocols and bioinformatics tools are constantly being developed to overcome initial limitations.Despite the as yet undiscussed advantages,however,there are still some challenges in data analysis and the interpretation of variants.In this review,we address the current state of next generation sequencing diagnostic testing for inherited human disorders,particularly giving an overview of the available high-throughput sequencing approaches;including targeted,whole-exome and whole-genome sequencing;and discussing the main critical aspects of the bioinformatic process,from raw data analysis to molecular diagnosis.
基金Bavarian State Ministry of Health and Care,Grant/Award Number:DMB-1805-0002。
文摘Although whole-exome sequencing and whole-genome sequencing has tremendously improved our understanding of the genetic etiology of human disorders,about half of the patients still do not receive a molecular diagnosis.The high fraction of variants with uncertain significance and the challenges of interpretation of noncoding variants have urged scientists to implement RNA sequencing(RNA-seq)in the diagnostic approach as a high throughput assay to complement genomic data with functional evidence.RNA-seq data can be used to identify aberrantly spliced genes,detect allele-specific expression,and identify gene expression outliers.Amongst eight studies utilizing RNA-seq,a mean diagnostic uplift of 15%has been reported.Here,we provide an overview of how RNA-seq has been implemented to aid in identifying the causal variants of Mendelian disorders.
文摘Introduction Acute liver failure(ALF)is an uncommon disease in pediatric cases.Etiology includes infections,autoimmune diseases,inborn errors of metabolism,and intoxications.Metabolic disorders account for 25%of resolved cases.However,the etiology remains unknown in half of pediatric ALF[1].The recognition of molecular etiopathogenesis has been facilitated after the common use of next-generation sequencing techniques.Recently,biallelic variants in neuroblastoma-amplified sequence(NBAS),Leucyl-tRNA synthetase 1(LARS1),and RAD50-interacting protein(RINT1)were identified in recurrent ALF(RALF)[2–4].
基金This cohort study is funded by the China National Natural Science Foundation(No.81970618)China National Clinical Research Centre Foundation(No.NCRC-2019-GP-02)+2 种基金Chongqing Science and Technology Commission project(No.cstc2016jcyjA0440)Chongqing Science and Technology plan project of Yuzhong District(No.2017045),Science and Technology Research Project of Chongqing Education Commission(No.KJZD-M201900401)the central government directs special funds for local science and technology development.
文摘Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome(NS)of different etiologies is critical for early clinical guidance.We employed whole-exome sequencing(WES)to detect monogenic causes of NS in a multicenter cohort of 637 patients.In this study,a genetic cause was identified in 30.0%of the idiopathic steroid-resistant nephrotic syndrome(SRNS)patients.Other than congenital nephrotic syndrome(CNS),there were no significant differences in the incidence of monogenic diseases based on the age at manifestation.Causative mutations were detected in 39.5%of patients with focal segmental glomerulosclerosis(FSGS)and 9.2%of those with minimal change disease(MCD).In terms of the patterns in patients with different types of steroid resistance,a single gene mutation was identified in 34.8%of patients with primary resistance,2.9%with secondary resistance,and 71.4%of children with multidrug resistance.Among the various intensified immunosuppressive therapies,tacrolimus(TAC)showed the highest response rate,with 49.7%of idiopathic SRNS patients achieving complete remission.Idiopathic SRNS patients with monogenic disease showed a similar multidrug resistance pattern,and only 31.4%of patients with monogenic disease achieved a partial remission on TAC.During an average 4.1-year follow-up,21.4%of idiopathic SRNS patients with monogenic disease progressed to end-stage renal disease(ESRD).Collectively,this study provides evidence that genetic testing is necessary for presumed steroid-resistant and idiopathic SRNS patients,especially those with primary and/or multidrug resistance.
基金supported by the Department of Biotechnology under Grant BT/NNT/28/SP18830/2018.
文摘Background:Leber congenital amaurosis(LCA),primarily characterized by retinal degeneration is the most severe form of inherited retinal dystrophy(IRD)responsible for congenital blindness.The presence of phenotypic heterogeneity makes the diagnosis of LCA challenging,especially in the absence of pronounced disease pathognomonic,yet it can be well comprehended by employing molecular diagnosis.Therefore,the present study aimed to reveal the causative mutations in ten LCA patients with variable phenotypes using clinical exome sequencing(CES).Methods:CES was performed in ten unrelated LCA patients.Ophthalmic information and family history of all patients were obtained to make a meaningful interpretation.The clinical exome data was analyzed and prioritized using a bioinformatics pipeline to identify mutations,which was further validated by Sanger sequencing.Segregation analysis was also performed on available family members.Results:CES led to the identification of causative mutations in nine LCA patients.Seven patients harbored a mutation in six LCA candidate genes,including RPE65,LCA5(n=2),CRX,PRPH2,CEP290,and ALMS1,while two patients possess a mutation in IFT80 and RP1,known to cause other diseases.Three novel mutations in LCA5(c.1823del),CRX(c.848del)and CEP290(c.2483G>T)were identified.The current study reports for the first time,a mutation in PRPH2,CEP290,and ALMS1 from the Indian population.Additionally,we observed a novel association of LCA phenotype with IFT80 known to cause Jeune syndrome.Based on the genetic finding,the patient AS09,who harbored a mutation in the RP1 gene,was re-diagnosed with early-onset retinitis pigmentosa.Conclusion:In conclusion,the results underline the importance of CES in clinically diagnosed LCA patients with variable phenotypes.The correlation between mutations in candidate genes and clinical phenotypes,helps to refine the clinical diagnosis.However,molecular evaluation with a larger cohort of LCA patients is needed for better understanding of the mutational spectrum in southern Ind
基金supported by grants to HX from University Grants Council(SRF116SC01UROP18SC06+10 种基金UROP20SC07)Innovation and Technology Commission(ITS/085/10ITS113/15FPITCPD/17-9ITT/023/17GPITT/026/18GP)of Hong Kong SARShenzhen Municipal Council of Science and Technology,Guangdong(JCYJ20170818113656988)Guangdong Province Basic and Applied Basic Research Fund(2021A1515011169)Shandong Province First Class Disciple Development Grant and Tai-Shan Scholar Program,Shandongand Ministry of Science and Technology(National Science and Technology Major Project,No.2017ZX09301064,2017ZX09301064004)People’s Republic of China,as well as grants from National Natural Science Foundation of China to M.Q.(8157151623)and J.W.(81603510)。
文摘Premenstrual dysphoric disorder(PMDD) affects nearly 5% of women of reproductive age. Symptomatic heterogeneity, together with largely unknown genetics, has greatly hindered its effective treatment. In the present study, analysis of genomic sequencing-based copy number variations(CNVs) called from 100 kb white blood cell DNA sequence windows by means of semisupervized clustering led to the segregation of patient genomes into the D and V groups, which correlated with the depression and invasion clinical types,respectively, with 89.0% consistency. Application of diagnostic CNV features selected using the correlation-based machine learning method enabled the classification of the CNVs obtained into the D group, V group, total patient group, and control group with an average accuracy of 83.0%. The power of the diagnostic CNV features was 0.98 on average, suggesting that these CNV features could be used for the molecular diagnosis of the major clinical types of PMDD. This demonstrated concordance between the CNV profiles and clinical types of PMDD supported the validity of symptom-based diagnosis of PMDD for differentiating between its two major clinical types, as well as the predominantly genetic nature of PMDD with a host of overlaps between multiple susceptibility genes/pathways and the diagnostic CNV features as indicators of involvement in PMDD etiology.
基金This study was supported by the National Natural Science Foundation of China(grant numbers:81870747,81860194,and 31771619)Beijing Municipal Natural Science Foundation(grant number:7182184).
文摘The Patched 1(PTCH1)gene encodes a membrane receptor involved in the Hedge-hog(Hh)signaling pathway,an abnormal state of which may result in congenital defects or hu-man tumors.In this study,we conducted whole-exome sequencing on a three-generation Chinese family characterized with variable penetrance of orofacial clefts.A rare heterozygous variant in the PTCH1 gene(c.2833C>T p.R945X)was identified as a disease-associated mutation.Structural modeling revealed a truncation starting from the middle of the second extracellular domain of PTCH1 protein.This may damage its ligand recognition and sterol transportation abilities,thereby affecting the Hh signaling pathway.Biochemical assays indi-cated that the R945X protein had reduced stability compared to the wild-type in vitro.In addi-tion,we reviewed the locations and mutation types of PTCH1 variants in individuals with clefting phenotypes,and analyzed the associations between clefts and locations or types of variants within PTCH1.Our findings provide further evidence that PTCH1 variants result in or-ofacial clefts,and contributed to genetic counseling and clinical surveillance in this family.
基金supported by the National Natural Science Founda-tion of China(Grant Nos.81822030 and 82072391 to N.W.,81930068 and 81772299 to Z.W.,81772301 and 81972132 to G.Q.,81672123 and 81972037 to J.Z.)Beijing Natural Science Foundation(Grant Nos.JQ20032 to N.W.,and 7191007 to Z.W.)+1 种基金Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program,Non-profit Central Research Institute Fund of Chinese Academy of Med-ical Sciences(Grant No.2019PT320025)the National Undergradu-ates Innovation and Training Program of Peking Union Medical College(Grant Nos.202010023022 to S.Z.).
文摘Developments in genetics and genomics are progressing at an unprecedented speed.Twenty years ago,the human genome project provided the first glimpses into the human genome sequence and launched a new era of human genetics.The emerging of next-generation sequencing(NGS)in 2005 then made possible comprehensive genetic testing such as exome sequencing and genome sequencing.Meanwhile,great efforts have been put into the optimization of bioinformatic pipelines to make increasingly speedy and accurate variant analyses based on NGS data.These advances in sequencing technologies and analytical methods have revolutionized the diagnostic odyssey of suspected hereditary diseases.More recently,the genotype-phenotype relationship and polygenic risk scores(PRSs)generated from genome-wide association studies have expanded our horizon from rare genetic mutations to a genomic landscape implicated by the combined effect of both rare variants and polymorphisms.At the same time,clinicians and genetic counselors are facing huge challenges conferred by overwhelming genomic knowledge and long sheets of testing reports for comprehensive genomic sequencing.The path toward the“next-generation”clinical genetics and genomics may underlie semiautomatic pipelines assisted by artificial intelligence techniques.
